N-substituted-3-azabicyclo [3:3:0] octane-2, 4-diones and salts thereof



United States Patent N-SUBSTITUTED-S-AZABICYCLO [3:3:0] OCTANE- 2,4-DIONES AND SALTS THEREOF Leonard M. Rice, Baltimore, Md., and Charles H. Grogan, Falls Church, Va., assignors to The Geschickter Fund for Medical Research, Inc., Washington, D.C., a corporation of New York No Drawing. Application January 28, 1957 Serial No. 636,469

'11 Claims. (Cl. 260-2471) This invention relates to compositons of matter, particularly to chemo-therapeutic organic componds that are also of value as synthetic and pharmaceutical intermediates in preparing other chemo-therapeutic agents. More particularly the invention relates to compounds possessing bronchiodilatory, antispasmodic and local anesthetic properties in varying degrees.

Specifically this invention relates to dialkylaminoalkyl imides and heterocyclic aminoalkyl imides of 1,2-ciscyclopentane dicarboxylic anhydride, their simple and quaternary salts.

It is a basic object of the present invention to provide novel organic compounds and methods for the preparation thereof.

It is another object of the invention to provide novel, physiologically active compounds characterized by chemotherapeutic or medicinal properties, particularly bronchiodilatory, antispasmodic and local anesthetic activity.

These and other objects and the manner in which they are accomplished will become apparent to those conversant with the art from the following description of the general class of compounds and certain specific examples'of particular members thereof as well as general and specific methods of their preparation.

Generally stated, the novel compounds discovered are obtained by reacting the appropriate dialkylaminoalkylamine or heterocyclic aminoalkyl amine with the anhydride of 1,2-cis-cyclopentane dicarboxylic acid to form the intermediate amic acid wihch is cyclizcd to the imide by heating for '2 hours at 170180 C. The imides are isolated directly from the reaction mixture by vacuum distillation and may be then converted to acid addition or quaternary salts by reaction with an acid, an alkyl halide or an alkyl sulfate such as dimethyl sulfate, methyl hydrogen sulfate, or methyl tolulene sulphate, respectively, in suitable media.

Formula I shows the general structural formula of compounds obtained by the methods hereafter more particularly described.

Formula I Formula II In these formulae A represents the azabicyclooctanedione nucleus, n a number from 1 to 6, R represents 2 alkyl groups with from 1 to 6 carbon atoms, and R an alkyl group with from 1 to 6 carbon atoms or an alkenyl group containing 3 to 6 carbon atoms, such as the allyl radical. The structure (N=R) may represent a heterocyclic ring namely, morpholine, piperidine, pyrrolidine, piperazine or N-methyl piperazine. X represents an anion, such as chloride, iodide, bromide, acetate, sulfate, hydrogen sulfate, methyl sulfate, tolulene sulphate, mucate, and theophyllinate. In the quaternary salts R may be the same as or different from R in any of the formulae given.

The compounds of the invention, the imides and the salts thereof, are therapeutically useful as bronchiodilatory and antispasmodic agents and as local anesthetics.

Also, the imides of the invention are useful as intermediates in that they may be reduced, as with lithium aluminum hydride, to the N-dialkylaminoalkyl-3-azabicyclooctane [3:310] bases and N-heterocyclicarmnoalkyl- 3-azabicyclooctane [3:310] bases described and claimed in our copending application Serial No. 636,511 filed concurrently herewith.

.The following examples of specific compounds and methods of their preparation will illustrate the manner in which they are obtained by the application of the general synthesizing procedure to particular members of the class of compounds discovered. It will be understood, however, that the following examples are merely illustrative and are not, nor are they intended to be, exhaustive of all the compounds embraced by this invention.

EXAMPLE I N-dimethylamin0ethyl-3-azabicycl0 [33:0] octane-2,4- dione, acid addition salts and quaternary salts 0.2 mole (28 gm.) of 1,2-cis-cyclopentane dicarboxylic anhydride was weighed into a 50 ml. 24/40 flask and 0.2 mole (17.6 gm.) of dimethylaminoethylamine was added rapidly in one lot. An exothermic reaction took place and the mass soon liquefied. It was stirred until homogeneous (or heated if necessary to obtain a homogeneous liquid phase) and reweighed. Any amine lost (usually none) was replaced and a 12% excess of amine added. The reaction mixture was stirred until again homogeneous and heated slowly to -180 C. It was maintained at this temperature until water was no longer evolved (usually 2 hours) to cyclize the amic acid initially formed to the imide. Following the heating period, the flask was connected directly to a vacuum distillation apparatus and heated slowly to the boiling point so as to remove any lower boiling material such as unreacted amine. The material was distilled and the whole distillled between 9398 C. at 0.3 mm. as a clear colorless oily liquid weighing 35.2 gm., n =1.4958.

The monohydrochloride.-.This was obtained as a white crystalline material by adding an excess of an ethanol solution of I-ICl to the imide dissolved in a minimum amount of isopropanol and "precipitation with anhydrous under Example I yielded 23 grams of the title imide, B.P. 108-113 C./0.08 mm.: n =1.4908.

ether. It had a melting point of 198-199 C. Recrystal- P t P t P t lization from isopropanol gave a melting point of 5 Analysis 3%; 933;, ffff 199199.5 C.

Ionic chloride: Calculated- 14.37%- FO 11(1 C l l t 3. 9 59, 11 10 143 5% Found 66.87 g 9.54 11. 57

The monomethi0dide.-The monometbiodide was ob- I Mined as a White. crystalline i i p l a slight 10 The monohydiochloride-This was formed from the excess of methyl g the fi i g' imide in isopropanol with an excess of alcoholic-H01 and It melted at .179 181 Reqryst om precipitation with ether, M.P. 122-124 C. not changed lute ethanol increased the melting point to 180-181 C. (m recrystallization =lonicchloridezCalculated-12.28%. Found- 12.56%.

EXAMPLE H 15 The m0n0mezhi0dide.This was formed from the imide in acetone with a slight excess of methyl iodide,

N-diethylaminoethyl--azabicyclo [33:0] octane 2,4- i f U after 2 recrystalhzaflonsdiam, acid addition and quaternary Salts Ionic iodide: Oalculated32.l8%. Found-32.02%.

The imide.-This imide was prepared in a manner anal- EXAMPLE V ogous to that detailed under Example I by the reaction of 0.2 mole of diethylaminoethylamine with 0.2 mole N mar p 225 Z5; 5 222 23; 5233 gz g of the anhydride. On vacuum distillatlon 39 grams of q W a fiolofless 5 hqmd 105-1150 6/03 was 25 The imide.-This was formed by reaction of 0.1 mole tamed 214930 of morpholinopropylamine with 0.1 mole of the anhy- P t P t P t d-ride as detailed under Example I. Obtained 24 grams Analysis gfgg ggg g B.P. l45-l55 C./0.08 mm.: It =l.5115.

Calculated 65. 51 9.31 11. 76 t P Found 6556 11-51 Analysis oir gn rr stiigggn miig iit The monohydrochloride.-This was obtained from the Calculated 63.13 2.33 10.52

imide as detailed under Example I as a white crystalline Found 63-59 10-47 material, M.P. 181183 c. The material crystallized from ethyl acetate isopropanol M.P. 183-185 C. The monoh d H r v i i y r001 on e.-Th1s Was formed .from the Iomc chlonde: Q f 'f imide in isopropanol with excess alcoholic-H01 and was The monomethzodlde.0bta1ned from the amide as de/ a White crystalline material, 1834 tallied under Example I as an 011 Whlch Wwld not 40 tallized from isopropano-l-ethyl ether, M.P. 1 84-185 c.

talhze' Ionic chloride: "Calculated-'1 1.7 1 Found-ll;66%

EXAMPLE III The m0nomethi0dide.-This was 'formed'ironi the N-dimethylaminopropyl-3-azabicyclo [33:0] octane-2,4- z g :fifiig: z gfi fig gggg i -fii iggj g dlone acld addition quaternary salts with decomposition. Recrystallized frem isopropanol,

prczpy la ii ii ne WIE i fZ EIO lZ f tl ie irihfidr i dz i il g il g Ionic iodide: Calculated-30.97%. Found-31:08%.

under Example I yielded 372 grams of the title imide, While the preparation of the hydrochloride acid addi- C. m1 mm "DZOZL494O. tion salt has been illustrated in the examples, other acid addition salts such as the hydrobromide, hydroiedide, Percent Percent Percent acetate, sulfate, mucate, and 'theop'hyllinate may be pre- Analysis Carbon Hydrogen Nitrogen pared in a manner similar to the illustrated preparation of the hydrochloride.

Calculated 64.25 8.99 12. 49 Similarly, while the preparation of the -'methiodide Found 64'48 13 quaternary salt has been illustrated in the examples,

, other quaternary salts such as the metho'chloride, metho- T drochlonfl e" Th1s W fomed iron? bromide, dimetho-sulfate, mettle-hydrogen sulfate, and

. qsopro'panol Wlth lalcohoilc'Hcl i preclpita' metho-tol-uene sulfate may be prepared in a manner simit i fg i gj y j i clgstamile i lar to the illustrated preparation of the methiodide.

1731740 ecrys a 1011 lsopropano To form the quaternary salts where the anion is acetate, mucate, theophyllinate and other Weak acid anions, Iomc chloride: Calculated-13.60%. Found-13.70%. the quatemaw halide may be first formed and then i monomethwdlde'obtamfiid from {1.16 lmlde. as treated with silver oxide or an ion exchange resin to redetailed under Example I-as a White crystalline material, move the halide The free quaternary base hydmxide .D c I e a a I 1:55 5 recrystalhzatwn Welded ma is next neutralized withthe appropriate weak acid such Q I k as acetic, mucic, theophyllin, etc.

101110 lodine. Calculated-34.65%. Found-34.61%. From the foregoing description of a novel class of EXAMPLE IV compounds, details of preparation andcharacterization of exemplary members of the class, it will be understood N-dieihylaminopropyl-S-azabicyclo {33:01 octane-2,4- that, on the basis f the discovery flndiknowledge dione, acid addition and quaternary salts closed herein, other specific compounds can beimade and variations in the methods "of s'ynthesis' re'sorted to. The

The imideF-Reaction of 0.1 mole of diethylaminofollowing table contains additionaljexamples of imides propylamine with 0.1 mole of-thea'nhydride as detailed 7 prepared by-the procedures-detailed herein.

N -DIETHYLAMIN OHEXYL-3-AZABICYCLO [3:53:01 OCTANE 2,4-DIONE [B.P. 128-134" C. at 0.1 mm.]

Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 69, 35 10, 27 9. 52 Found 69.08 10. 52 9, 43

N-DIHEXYLAMINOETHYL-3-AZABICYCLO [3:3z0]

O CTANE-2,4DIONE [B.P. 134144 C. at 0.1 mm.]

N-PYRROLIDINOETHYL-B-AZABICYCLO [3:3z0] OCTANE-2,4-DIONE [B.P. 134-139 O. at 0.2 mm. pressure] Percent Percent Percent Carbon Hydrogen Nitrogen Calculated 66, 07 8, 53 11. 86 Found 66, 02 8. 56 11. 77

The specific compounds and methods disclosed herein are to be considered in all respects as illustrative and not restrictive, the scope of the discovery being indicated by the appended claims rather than the foregoing descriptive detailed examples, and all specific compounds and variations and methods which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

What is claimed and desired to be secured by United States Letters Patent is:

1. As a novel composition of matter, a compound selected from the group consisting of (1) N-substituted derivatives of 3-azabicyc1o [3:3:0] octane-2, 4-diones having the general formula where in said formula, n is a number from 1 to 6, and R is selected from the group consisting of two alkyl groups with each alkyl group having from 1 to 6 carbon atoms and a radical forming together with the nitrogen atom to Which it is attached, a heterocyclic group selected from the group consisting of morpholino, piperidino, piperazino, methylpiperazino and pyrrolidino, and (2) acid addition salts and quaternary salts of (1).

2. As a novel composition of matter, a methonium salt of N-dimethylaminoethyl-3-azabicyc1o [323:0] octane-2,4-dione.

3. As a novel composition of matter, a methonium salt of N-diethylaminoethyl-3-azabicyclo [3:3z0] octane-2, 4-dione.

4. As a novel compoistion of matter, a methonium salt of N-dimethylarninopropyl-3-azabicyclo [3:3z0] octane-2,4-dione.

5. As a novel composition of matter a methonium salt of N-diethylaminopropyl-3-azabicyclo [3:3z0] octane-2,4-dione.

6. As a novel composition of matter, a methonium salt of N-morpholinopropyl-3-azabicyclo [323:0] octane- 2,4-dione.

7. As a novel composition of matter, N-dimethylaminoethyl-3-azabicyclo [3 :3 :0] octane-2,4-dione.

8. As a novel composition of matter, the methonium chloride of N-dimethylaminoethyl-3-azabicyclo [3:3:0] octane-2,4-dione.

9. As a novel composition of matter, N-dimethylaminopropyl-3-azabicyclo [3 :3 :0] octane-2,4-dio11e.

10. As a novel composition of matter, the methonium chloride of N-dimethylaminopropyl-3-azabicyclo [3:310] octane-2,4-dione.

11. As a novel composition of matter, N-diethylaminoethyl-3 -azabicyc1o [3 :3 :0] octane-2,4-dione.

References Cited in the file of this patent UNITED STATES PATENTS 2,541,211 Cusic et al. Feb. 13, 1951 2,743,270 Blicke Apr. 24, 1956 2,745,836 Suter May 15, 1956 2,784,199 Grogan et al. Mar. 5, 1957 2,786,834 Grogan et al. Mar. 26, 1957 2,802,004 Grogan et al Aug. 6, 1957 FOREIGN PATENTS 1,108,117 France Aug. 24, 1955 

1. AS A NOVEL COMPOSITION OF MATTER, A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) N-SUBSTITUTED DERIVATIVES OF 3-AZABICYCLO (3:3:0) OCTANE-2, 4-DIONES HAVING THE GENERAL FORMULA
 6. AS A NOVEL COMPOSITION OF MATTER, A METHONIUM SALT OF N-MORPHOLINOPROPYL-3-AZABICYCLO (3:3:0) OCTANE2,4-DIONE. 